A young woman with membranoproliferative glomerulonephritis and persistent hypocomplementemia: a case report

Abstract

A young woman presented with a 17-year history of proteinuria, hematuria with persistent hypocomplementemia. She has been followed up for 2 years. The patient underwent comprehensive diagnostic evaluation, including two renal biopsies. The initial biopsy indicated membranoproliferative glomerulonephritis (MPGN), while the subsequent biopsy revealed concurrent thrombotic microangiopathy (TMA) kidney injury, suggesting a complement-mediated disorder. Genetic testing identified two heterozygous missense variants, c.848A > G (p.Asp283Gly) and c.1339C > T (p.Pro447Ser), in the Complement factor I (CFI) gene. Both are classified as variants of uncertain significance, suggestive of potential susceptibility to complement dysregulation. The clinical diagnosis was MPGN with overlapping TMA. Treatment with mycophenolate mofetil and losartan potassium resulted in reduced urinary protein, improved complement levels, and stabilized renal function; traditional Chinese herbal medicine was administered as supportive therapy. This case highlights the diagnostic challenges, when renal pathology indicates membranoproliferative-like lesions that cannot be explained by Ig-mediated or C3 glomerulopathy, especially accompanied by TMA lesions or persistent hypocomplementemia, complement system-related tests including complement regulatory gene mutation may helpful to establish the etiological diagnosis and guide management.

Introduction

Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury characterized by mesangial hypercellularity and capillary wall thickening, currently classified into immune-complex-mediated and complement-mediated forms based on underlying pathophysiology. [1] Thrombotic microangiopathy (TMA) manifests in diverse forms, characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ damage, including acute kidney injury [2]. Pathologically, TMA is defined by vascular damage, including arteriolar and capillary thrombosis, endothelial abnormalities, and vessel wall changes [3]. Although TMA and MPGN exhibit distinct pathological features, both are classified as complement-mediated disorders based on their etiology. Such diseases often have a protracted course and recurrent episodes, and repeated renal biopsy results in the same patient may undergo some changes.

We report a rare case of a young Chinese woman diagnosed with MPGN via initial renal biopsy, with a subsequent biopsy revealing concurrent TMA. Genetic testing identified two heterozygous missense variants, c.848A > G (p.Asp283Gly) and c.1339C > T (p.Pro447Ser), in the Complement factor I (CFI) gene, classified as variants of uncertain significance, suggestive of potential susceptibility to complement dysregulation. The final clinical diagnosis was MPGN with overlapping TMA.

Case report

A 30-year-old Chinese woman presented to our hospital in 2023 with a 17-year history of proteinuria and hematuria, accompanied by a 1-year history of elevated serum creatinine. The patient’s renal disease first manifested in 2006 as nephrotic syndrome with significant erythrocyturia; steroids treatment provided minimal relief. In 2009, a renal biopsy at a local hospital revealed membranoproliferative glomerulonephritis (MPGN), focal glomerulosclerosis, and mild tubulointerstitial disease. Immunohistochemical staining demonstrated focal, segmental, and mesangial positivity for IgG and IgM (+); IgA was focally mild to moderately positive (++); and C3d was diffusely positive (+), with strong positivity in capillary loops (+-++). Light microscopy of the 36 glomeruli revealed global sclerosis in three, segmental sclerosis in one, diffuse double contours of the basement membranes, and moderate mesangial proliferation. Clinical investigations ruled out autoimmune diseases such as systemic lupus erythematosus (SLE), as well as secondary renal damage caused by infections such as viral hepatitis and infective endocarditis. The patient achieved complete remission of proteinuria following treatment with methylprednisolone (750 mg/d for 3 days), cyclophosphamide pulse therapy (cumulative dose 5.6 g), captopril, and prednisone (35 mg qod). The urinary total protein (UTP) level declined to a nadir of 0.28 g per day with slight microscopic hematuria. Prednisone was subsequently tapered and discontinued.

In 2016, she experienced relapse with edema, proteinuria (3.2 g/d), hematuria. Immunological evaluation revealed hypocomplementemia with reduced C3 (0.51 g/L), normal C4 (0.22 g/L) and normal total complement activity (CH50 49.3 U/mL). Autoimmune diseases and infection-related nephritis were excluded again. Treatment with mycophenolate mofetil (MMF) 0.5 g bid and prednisone (10–15 mg/d) reduced proteinuria to 0.16 g/d by 2020, with stable serum creatinine (SCr) (82 µmol/L) and mild anemia (HGB 90 g/L). She reported frequent colds and diarrhea but no other symptoms. After discontinuing MMF and prednisone, losartan potassium (50 mg qd) was continued. Thirty-one months after immunosuppressant withdrawal, SCr showed an upward trend (118 μmol/L) with UTP increasing to 0.3–0.45 g/24 h and reduced C3 (0.51 g/L).

Persistent hypocomplementemia and progressive decline in renal function prompted hospitalization. Additional immunological and hematological evaluations were performed to investigate the etiology. Systematic evaluation ruled out secondary etiologies, including ANCA-associated vasculitis, SLE, antiphospholipid syndrome, cryoglobulinemia, HBV, HCV, Shiga toxin-mediated hemolytic uremic syndrome, and monoclonal gammopathies. A second renal biopsy was performed in May 2023. Immunofluorescence staining was qualitatively assessed, showing IgM (++) (Fig. 1g), IgA (±), and C3 (±) (Fig. 1f) deposition in the capillary walls and mesangium, IgG, C1q, FRA, Alb, κ and λ were all negative. Immunofluorescence for IgG on protease-digested paraffin sections was remained negative. Light microscopy revealed ischemic sclerosis in 17 of 28 glomeruli (with one globally sclerosed), moderate diffuse mesangial proliferation and matrix expansion in the remaining glomeruli, segmental mesangial interposition (Fig. 1d), increased intracapillary cells, basement membrane thickening, partial double contours of capillary walls (Fig. 1c), wire-loop lesions (Fig. 1e), and mesangial lysis with microaneurysm-like capillary loop expansion (Fig. 1b). Focal cellular infiltration, tubular atrophy and interstitial fibrosis were in the tubulointerstitium. Arteriolar wall thickening with hyalinization, intimal fibrotic hyperplasia and sclerosis, and luminal stenosis. Electron microscopy revealed electron-dense deposits in subendothelial, mesangial, and subepithelial locations, along with extensive foot process effacement, significant widening of the lamina densa interna in the GBM (Fig. 1h), and segmental double contours (Fig. 1i). Pathologic diagnosis: 1. Membranoproliferative glomerulonephritis; 2. Thrombotic microangiopathy renal injury.

Fig. 1.

Pathological findings of the second renal biopsy. Light microscopy revealed (a) ischemic glomerulosclerosis (arrow) (PASM+Masson × 40), (b) mesangial lysis with capillary loop microangioma like expansion(PASM+Masson × 200), (c) double contour formation (PASM+Masson × 400), (d) moderate diffuse mesangial hypercellularity and matrix expansion, with segmental mesangial insertion (arrow) (HE × 400). (e) Wire-loop lesions (Masson × 400). Immunofluorescence staining for (f) C3 is weakly positive (±) in the mesangium, and for (g) IgM is positive(++) in the mesangium and along the basement membrane. Electron microscopy: (h) widening of the lamina dense interna (black arrow) and subendothelial electron-dense deposits (red arrow). (i) Double contour formation of glomerular basement membrane (arrow)

Following the biopsy, detailed hematological evaluation was performed to assess for systemic involvement. Despite the presence of TMA lesions, there was no evidence of systemic microangiopathic hemolysis, indicated by normal platelet counts (194 × 10⁹/L), normal lactate dehydrogenase (LDH 215 U/L, normal <247), and normal indirect bilirubin (4.0 μmol/L), with no schistocytes observed on the peripheral smear. Investigation into the mild anemia revealed an iron profile consistent with anemia of chronic disease rather than iron deficiency or hemolysis, characterized by low serum iron (4.06 μmol/L, normal 9–27) and low transferrin (164.58 mg/dL, normal 200–400), but elevated serum ferritin (136.98 μg/L, normal 10–120). To further differentiate the etiology, the activity of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was measured at 90%, effectively ruling out thrombotic thrombocytopenic purpura. Additionally, serum complement Factor H levels were normal (521.2 μg/ml), and tests for anti-Factor H antibodies were negative, combined with the extensive negative autoimmune screening mentioned above, making autoimmune-mediated atypical hemolytic uremic syndrome (aHUS) unlikely. These findings, confirming localized histological injury without systemic hematologic abnormalities, supported a clinical diagnosis of renal-limited TMA. Prompted by this specific combination of biopsy-proven TMA, absence of systemic hemolysis, and long-standing hypocomplementemia, complement regulatory gene testing was performed. The patient was administered MMF at 0.5 g in the morning and 0.25 g in the evening. After treatment, the patient’s UTP decreased to 0.24 g/d, with C3 improving to 0.69 g/L. The dosage of MMF was reduced to 0.25 g bid and losartan potassium (50 mg qd) was resumed with Chinese herbal medicine and iron preparation added as supportive therapy; no relapses have been reported since then. At the most recent follow-up in 2025 (now aged 32), her serum C3 was 0.67 g/L, UTP was 0.14 g/day and SCr was 86 μmol/L (Table 1, Fig. 2).

Table 1.

Longitudinal laboratory parameters and treatment regimen

Parameter	Reference Range	2009	2016	2020	May 2023	July 2023	2025
Clinical stage		1st biopsy	Relapse	After immunosuppression withdrawal	Pre-2nd biopsy status	Post-2nd biopsy Treatment	follow-up
SCr (μmol/L)	45–84	–	75.3	82	118	98	86
eGFR (mL/min/1.73 m2)	>90	–	96.32	84.49	53.27	66.69	77.0
UTP (g/d)	<0.15	0.28	3.2	0.16	0.45	0.24	0.14
C3 (g/L)	0.9–1.8	–	0.51	–	0.51	0.69	0.67
C4 (g/L)	0.1–0.4	–	0.15	–	0.30	0.29	0.29
CH50 (U/ml)	23–62	–	–	–	53.5	57.0	40.7
Hb (g/L)	115–150	107	110	97	91	98	108
Immunosuppression	–	Methylprednisolone 750 mg/d × 3d IV → prednisone 35 mg qod + Cyclophosphamide 5.6 g	Prednisone (10–15 mg/d) + MMF 0.5 g bid	–		MMF (0.5 g AM/0.25 g PM)	MMF 0.25 g bid
Adjunctive Therapy	–	Captopril 37.5 mg q8h	–	Losartan 50 mg qd		Losartan 50 mg qd + chinese herbal medicine + iron preparation

Abbreviations: MMF, mycophenolate mofetil; IV, intravenous; qd, once daily; bid, twice daily; qod, every other day; AM, morning; PM, evening; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; UTP, urinary total protein; Hb, hemoglobin; C3, complement component 3; C4, complement component 4; CH50, total complement activity.

Dash (–) indicates absence.

Fig. 2.

Clinical course and treatment timeline. Abbreviations: MMF, mycophenolate mofetil; bid, twice daily; qd, once daily; qod, every other day; AM, morning; PM, evening; SCr, serum creatinine; Hb, hemoglobin; C3, complement component 3; UTP, urinary total protein

Genetic testing, performed via next-generation sequencing for the proband and validated by Sanger sequencing for the family, identified two heterozygous CFI variants. Zygosity was confirmed by analyzing sequencing depth and allele frequency. The first variant, c.848A > G (p.Asp283Gly, dbSNP: rs756201106) was inherited from the mother, while the second, c.1339C > T (p.Pro447Ser), was inherited from the father (Fig. 3). According to the American College of Medical Genetics and Genomics (ACMG) guidelines [4], the c.848A > G (p.Asp283Gly) variant is classified as a variant of uncertain significance (VUS) but is suggestive of potential deleterious effects. This assessment is supported by criteria PM2_Supporting (extremely rare in population databases, allele frequency 0.00038) and PP3_Strong (deleterious predictions by multiple in silico tools including REVEL, SIFT, and PolyPhen-2). The c.1339C > T (p.Pro447Ser) variant is also classified as VUS. While it meets criteria PM2_Supporting (rare allele frequency 0.00011), some computational models suggest benignity (BP4). (Table 2). However, in this compound heterozygous context, it may act as a potential genetic modifier. The patient is an only child. Both parents are phenotypically normal with no history of renal disease or autoimmune disorders.

Fig. 3.

Pedigree and chromatograms of CFI gene sequence alterations. The patient’s mother and father are heterozygous for the c.848A > G and c.1339 C > T variants, respectively; the patient is compound heterozygous for both variants. Abbreviations: HET, heterozygous variants; WT, wild-type

Table 2.

Summary of complement factor I variants identified in the proband

Variant	Domain	Predicted effect	Evidence	Inheritance
c.848A > G (p.Asp283Gly)	LDL receptor-like domain (exon 6)	Missense; VUS/potentially deleterious	ACMG VUS (PM2_Supporting+ PP3_Strong); REVEL/SIFT/PolyPhen-2 damaging; ClinVar: Uncertain significance	Maternal heterozygous
c.1339C > T (p.Pro447Ser)	Serine protease domain (exon 11)	Missense; VUS/likely benign	ACMG VUS (PM2_Supporting + BP4); REVEL/SIFT/PolyPhen-2 benign; ClinVar: Uncertain significance	Paternal heterozygous

Abbreviations: VUS, variant of uncertain significance; ACMG, American College of Medical Genetics and Genomics; PM2_Supporting, absent from or extremely rare in population databases (supporting evidence of pathogenicity); PP3_Strong, multiple lines of computational evidence support a deleterious effect (strong evidence of pathogenicity); BP4, multiple lines of computational evidence suggest no impact on the gene or gene product (supporting evidence of benignity); REVEL, Rare Exome Variant Ensemble Learner; SIFT, Sorting Intolerant From Tolerant; PolyPhen-2, Polymorphism Phenotyping v2; GERP+, Genomic Evolutionary Rate Profiling (rejected substitutions); ClinVar, Clinical Variant database

Discussion

MPGN is classified by immunofluorescence into immune-complex-mediated forms (dominant Ig) or complement-mediated forms (C3-dominant with minimal Ig), the latter encompassing C3 glomerulopathy (C3G) and dense-deposit disease [1]. Differential diagnosis requires excluding immune-complex-mediated causes, such as infections, autoimmune diseases, and proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Comprehensive diagnostic evaluation including serologic assays, autoantibody panels, and electrophoresis is essential. In both biopsies, immune complex-mediated MPGN was excluded through comprehensive serological evaluation, and pronase-digested paraffin immunofluorescence in the second biopsy confirming absence of masked IgG deposits [5]. The observed IgM positivity is interpreted as nonspecific trapping associated with glomerular sclerosis and chronic injury, rather than etiologic immune complex deposition [6]. Persistently negative autoantibodies, together with low C3, normal C4 and CH50 levels, point to alternative complement pathway activation. This pattern helps to differentiate the condition from classical pathway-mediated disorders such as active SLE, where reduced C4 is typically observed [7, 8]. However, rather than fitting neatly into the classical definition of C3G, this case represents a complement-mediated MPGN-like pattern. This distinct presentation highlights a gap in the current classification system regarding cases that do not strictly meet C3G criteria yet show clear complement dysregulation. Although MPGN and TMA may coexist, as observed in this case, their causal relationship remains unclear; emerging evidence suggests that TMA and MPGN may represent a pathological continuum in the context of complement dysregulation [9, 10]. The initial MPGN pattern with prominent C3d deposition likely reflects chronic complement dysregulation causing indolent glomerular injury, whereas the superimposed renal-limited TMA without systemic microangiopathic hemolysis indicates aggravated complement activation leading to endothelial damage and microthrombosis confined to the glomerular microvasculature (Fig. 4). Persistent hypocomplementemia, proteinuria, and atypical features necessitate genetic testing to identify mutations in complement-regulating genes, guiding diagnosis and therapy.

Fig. 4.

Conceptual model of pathology evolution. Abbreviations: MPGN, membranoproliferative glomerulonephritis; TMA, thrombotic microangiopathy; CFI, complement factor I

The C3 convertase is regulated by complement proteins, including complement factor H (CFH), Membrane Cofactor Protein (MCP, CD46), and CFI, to prevent excessive C3b production. Mutations in these genes can disrupt this regulation, leading to uncontrolled complement activity and disease. [11, 12] CFI is a serine protease that downregulates complement activity in the fluid phase or on cell surface. Impaired CFI function is implicated in C3G and aHUS. In our patient, compound heterozygous CFI mutations exemplify this impairment. The CFI mutations c.848A > G (p.Asp283Gly) and c.1339C > T (p.Pro447Ser) are rarely reported in Chinese patients with concurrent MPGN and TMA. Recent studies have highlighted the clinical relevance of CFI variants in cohorts of patients with TMA and overlapping C3G phenotypes [13, 14]. Our findings align with these reports but present a unique long-term course. Specifically, the c.848A > G mutation (p.Asp283Gly) replaces an acidic aspartic acid with a neutral glycine in the LDL receptor class A domain. As supported by findings from Osawa et al. [15] regarding overlapping aHUS and C3G, Wen et al. [16] regarding post-transplant C3G and TMA, and Zhao et al.’s cohort study of C3G in Asia [17], this missense variant is predicted to disrupt Ca²⁺ binding sites, leading to protein misfolding, reduced C3b affinity, and diminished FI cofactor activity [18, 19], thereby promoting complement alternative pathway dysregulation. Regarding the c.1339C > T (p.Pro447Ser) variant, it substitutes a rigid proline with a polar serine in the trypsin-like serine protease domain of CFI. While unlikely to cause gross morphological changes to the protein, this substitution disrupts structural kinks and may induce subtle conformational alterations. These alterations potentially reduce proteolytic efficiency for C3b cleavage, acting as a genetic modifier [13, 20–22].

The distinct renal-limited TMA phenotype in our patient, in contrast to systemic aHUS, may be attributed to the specific functional consequences of these missense variants. Unlike loss-of-function nonsense mutations that often precipitate systemic thrombotic events, these missense variants such as p.Asp283Gly and p.Pro447Ser likely retain residual FI secretion and function sufficient to prevent widespread systemic thrombosis but inadequate to control complement activation under local renal microenvironmental stress [23]. This scenario is consistent with chronic MPGN-like glomerular injury with episodic exacerbation leading to localized endothelial damage and TMA, as supported by mouse models where analogous variants exacerbate C3 deposition only under inflammatory triggers without spontaneous systemic disease [24]. Notably, in kidney-limited TMA cohorts, complement defects predominate, often associated with better outcomes than systemic forms due to the absence of widespread thrombosis [25, 26]. Persistent hypocomplementemia reflects ongoing alternative pathway dysregulation driving proteinuria, endothelial injury, and progressive renal damage.

The patient has remained clinically stable on treatment with MMF and losartan potassium, supplemented with supportive Chinese herbal medicine. Although KDIGO guidelines recommend complement inhibition for complement-mediated glomerular diseases with active or progressive features, C5 inhibitors such as eculizumab or ravulizumab were considered but not initiated in this case due to the patient’s mild clinical manifestations and favorable response to current regimen [27]. This decision was guided primarily by the indolent, renal-limited clinical course and shared decision-making with the patient. However, should disease relapse occur with worsening proteinuria or declining renal function, emerging proximal complement inhibitors, such as the Factor B inhibitor iptacopan or C3 inhibitor pegcetacoplan, could be considered as potential therapeutic options based on recent evidence in C3 glomerulopathy and MPGN [28, 29].

Our study has certain limitations. First, limited accessibility of specialized complement assays in our region precluded the measurement of serum Factor I levels or cofactor activity, alternative pathway hemolytic activity (AH50), C3 nephritic factor (C3NeF) and tissue C5b-9 staining. Consequently, the functional relevance of the CFI variants was inferred based on clinical presentation, exclusion of other etiologies, and in silico predictions, rather than direct functional verification. Second, serial serum C3 levels were not consistently monitored during the clinical remission period (2009–2016) as the patient underwent maintenance follow-up at local facilities. Finally, as a single case report, the therapeutic efficacy is observational, and future functional studies are needed to definitively confirm the impact of these variants on complement regulation.

This case emphasizes the diagnostic challenges of overlapping MPGN and TMA associated with CFI gene mutations. Despite the absence of severe systemic TMA features, persistent proteinuria and hypocomplementemia necessitated sequential biopsies to monitor evolving renal pathology. Timely complement testing and genetic screening are critical for accurate diagnosis and tailored treatment, improving patient outcomes.

Abbreviations

MPGN

Membranoproliferative glomerulonephritis

TMA

Thrombotic microangiopathy

CFI

Complement factor I

SLE

Systemic lupus erythematosus

UTP

Urinary total protein

MMF

Mycophenolate mofetil

SCr

Serum creatinine

GBM

Glomerular basement membrane

C3G

C3 glomerulopathy

aHUS

Atypical hemolytic uremic syndrome

CH50

total complement activity

AH50

Alternative pathway hemolytic activity

C3NeF

C3 nephritic factor

ACMG

American College of Medical Genetics and Genomics

Author contributions

Data acquisition: SL, JL, HL,SZ and LL. Manuscript drafting: JL, HL. Critical revision: HL, SL, XR and JL. Manuscript approval: HL, JL, LL, XR and SL.

Funding

This research was supported by the Beijing Natural Science Foundation (Grant No. 7252259), the Central High-level Traditional Chinese Medicine Hospital Clinical Research and Achievement Transformation Ability Improvement Project of China (Grant No. HLCMHPP2023039), and the National Science and Technology Major Project of China (Grant No. 2023ZD0509303).

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent for participate

This study was conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences. Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

Consent for publication

Written informed consent was obtained from the patient for the publication of any related images or data included in this manuscript.

Competing interests

The authors declare no competing interests.